Potassium ion is the principal intracellular cation of most body tissues. Potassium ions participate in a number of essential physiological processes, including the maintenance of intracellular tonicity, the transmission of nerve impulses, the contraction of cardiac, skeletal, and smooth muscle and the maintenance of normal renal function.
Potassium depletion may occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops slowly as a consequence of prolonged therapy with oral diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Potassium depletion due to these causes is usually accompanied by a concomitant deficiency of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances of cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases flaccid paralysis and/or impaired ability to concentrate urine.
Potassium depletion associated with metabolic alkalosis is managed by correcting the fundamental causes of deficiency whenever possible and administering supplemental potassium chloride, in the form of high potassium food or potassium chloride solution, tablets or capsules.
Potassium chloride is conventionally administered in the form of tablets or capsules by the oral route. These dosage forms have the advantages of convenience and ease of administration. It is desired in potassium replacement therapy that the total body potassium level be restored to normal quickly and, for patient convenience, it is desirable that the normal level be sustained for a significant period of time.
The usual dietary intake of potassium by the average adult is 40 to 80 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 mEq or more of potassium from the total body store. Dosage must be adjusted to the individual needs of each patient but is typically in the range of 20 mEq per day for the prevention of hypokalemia and 40-100 mEq or more per day for the treatment of potassium depletion.
Potassium chloride, however, is a known gastrointestinal tract irritant, the most common adverse reactions to oral administration being nausea, vomiting, abdominal discomfort and diarrhea. Also, the administration of potassium salts, particularly in enteric-coated tablets, may cause intestinal ulceration, sometimes with hemorrhage and perforation or with the late formation of strictures. These symptoms are best prevented by either diluting a liquid preparation to a concentration that can be tolerated by the patient or providing a controlled release formulation to minimize the likelihood of producing high localized concentrations of potassium within the gastrointestinal tract. A second major problem associated with the administration of potassium chloride, even dilute liquid preparations thereof, is patient noncompliance due to the unpalatable taste of the liquid preparations.
Several controlled release tablet formulations for potassium chloride and other active ingredients are known in the art. For example, U.S. Pat. No. 3,538,214 discloses a controlled release formulation comprising a tablet core containing potassium chloride coated with a film of water-insoluble plastic and a film modifying material that is selectively soluble in either the stomach or intestinal fluids so that a membranous or dialytic type film remains when the film modifying material is dissolved in the gastrointestinal tract permitting the potassium chloride to leach out slowly. Also known is a slow release formulation in which a conventional tablet is encased in an impermeable membrane provided with a single aperture through which the active ingredient exits following administration to a patient. The release of active ingredient from the latter tablet formulation is determined by the rate of release of active ingredient from the aperture. Additionally, controlled release tablet formulations exist which are known as matrix tablets and which consist of polymeric material having an active ingredient dispersed therethrough. In use, the active ingredient diffuses out of the polymer matrix and the formulation ultimately breaks up completely.
Gastric irritation and gastric and intestinal ulcerations, however, have been reported following the use of several of the above sustained release formulations when the active ingredient is potassium chloride. It is believed that such formulations produce high concentrations of potassium that are localized within the gastrointestinal tract.
As discussed above, potassium chloride replacement therapy requires large dosages of potassium chloride, therefore it is desirable to produce a tablet wherein at least 80% of the total weight of the tablet is potassium chloride, otherwise the size of the tablet is increased to where it becomes difficult to swallow. Furthermore, it is also desirable to impart a sufficient degree of hardness to the tablet core without increasing the friability.
One of the disadvantages with the slow release formulation of U.S. Pat. No. 3,538,214 is that the maximum weight percent of potassium chloride per total weight of tablet is only 49%.
Belgium Pat. No. 900,824, granted October 31, 1984 in the name of the assignee of the present application, discloses a controlled release formulation for the release of potassium chloride through a differentially permeable membrane. The potassium chloride formulation disclosed therein, however, is for a tablet where the potassium chloride is about 66% of the total tablet weight.